Pharmacokinetics and pharmacodynamics of tiotropium solution and tiotropium powder in chronic obstructive pulmonary disease

J M Hohlfeld, A Sharma, J A van Noord, P J G Cornelissen, E Derom, L Towse, V Peterkin, B Disse, J M Hohlfeld, A Sharma, J A van Noord, P J G Cornelissen, E Derom, L Towse, V Peterkin, B Disse

Abstract

The aim of the study was to characterize pharmacokinetics of tiotropium solution 5 µg compared to powder 18 µg and assess dose-dependency of tiotropium solution pharmacodynamics in comparison to placebo. In total 154 patients with chronic obstructive pulmonary disease (COPD) were included in this multicenter, randomized, double-blind within-solution (1.25, 2.5, 5 µg, and placebo), and open-label powder 18 µg, crossover study, including 4-week treatment periods. Primary end points were peak plasma concentration (Cmax,ss ), and area under the plasma concentration-time profile (AUC0-6h,ss ), both at steady state. The pharmacodynamic response was assessed by serial spirometry (forced expiratory volume in 1 second/forced vital capacity). Safety was evaluated as adverse events and by electrocardiogram/Holter. Tiotropium was rapidly absorbed with a median tmax,ss of 5-7 minutes postdosing for both devices. The gMean ratio of solution 5 µg over powder 18 µg was 81% (90% confidence interval, 73-89%) for Cmax,ss and 76% (70-82%) for AUC0-6h,ss , indicating that bioequivalence was not established. Dose ordering for bronchodilation was observed. Powder 18 µg and solution 5 µg were most effective, providing comparable bronchodilation. All treatments were well tolerated with no apparent relation to dose or device. Comparable bronchodilator efficacy to powder18 µg at lower systemic exposure supports tiotropium solution 5 µg for maintenance treatment of COPD.

Trial registration: ClinicalTrials.gov NCT01222533.

Keywords: COPD; pharmacodynamics; pharmacokinetics; tiotropium HandiHaler®; tiotropium Respimat® SMI.

© 2013 The Authors. The Journal of Clinical Pharmacology Published by Wiley Periodicals, Inc. on behalf of The American College of Clinical Pharmacology.

Figures

Figure 1
Figure 1
Flow diagram, design, and patient disposition. A total of 210 patients were initially enrolled and screened. Following a 1-week run-in period, 154 patients were randomized to five treatment groups, for a 4-week period. The number of patients in each treatment group that comprised the treatment set (TS) and the pharmacokinetic set (PS) at randomization and study end is indicated. The number of patients in each treatment group who prematurely discontinued treatment, reported any adverse event (AE) or serious AE is also indicated in the figure. The result showed that tiotropium delivered either as a powder or solution was well tolerated.
Figure 2
Figure 2
Clinical study. (A) Geometric mean tiotropium plasma concentration–time profile following multiple inhalations as solution or as powder. (B) Comparison of maximum tiotropium plasma concentrations at steady state (Cmax,ss) by dose and device (solution versus powder). On day 26 of each treatment period, blood samples were collected 5 minutes before dosing and during a 6-hour period at 2, 5, 7, 9, 12, 15, 20, 30, 40, 60 minutes, and 2, 4, and 6 hours postdosing. Tiotropium concentrations were determined by a validated assay using high-performance liquid chromatography coupled to tandem mass spectrometry. (A) Mean plasma concentrations were (slightly) lower with tiotropium solution 5 µg compared with tiotropium powder 18 µg. (B) There was a dose-dependent increase in tiotropium plasma exposure as determined by Cmax.
Figure 3
Figure 3
Adjusted mean FEV1 over 6 hours at day 28. On day 28 of each treatment period, 2 days after the pharmacokinetic (PK) test day, serial 6-hour spirometry was conducted at 10 minutes before and at 30 and 60 minutes, and 2, 3, 4, 5, and 6 hours after inhalation of study medication. Tiotropium solution doses 1.25, 2.5, and 5 µg and tiotropium powder 18 µg provided significantly (P < .0001) greater bronchodilation compared to placebo in all spirometric end points. Within the first hour postdosing, tiotropium solution 2.5 µg provided less bronchodilatory effects compared with both solution 5 µg and powder 18 µg, while solution 5 µg and powder 18 µg were similar. FEV1, forced expiratory volume in 1 second.

References

    1. Celli BR, MacNee W. Standards for the diagnosis and treatment of patients with COPD: a summary of the ATS/ERS position paper. Eur Respir J. 2004;23(6):932–946.
    1. From the Global Strategy for the Diagnosis Management and Prevention of COPD, Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2011. Available from: . Last accessed April 2011.
    1. Bateman E, Singh D, Smith D, et al. Efficacy and safety of tiotropium Respimat SMI in COPD in two 1-year randomized studies. Int J Chron Obstruct Pulmon Dis. 2010;5:197–208.
    1. Bateman ED, Tashkin D, Siafakas N, et al. A one-year trial of tiotropium Respimat plus usual therapy in COPD patients. Respir Med. 2010;104(10):1460–1472.
    1. Maltais F, Hamilton A, Marciniuk D, et al. Improvements in symptom-limited exercise performance over 8 h with once-daily tiotropium in patients with COPD. Chest. 2005;128(3):1168–1178.
    1. Niewoehner DE, Rice K, Cote C, et al. Prevention of exacerbations of chronic obstructive pulmonary disease with tiotropium, a once-daily inhaled anticholinergic bronchodilator: a randomized trial. Ann Intern Med. 2005;143(5):317–326.
    1. Tashkin DP, Celli B, Senn S, et al. A 4-year trial of tiotropium in chronic obstructive pulmonary disease. N Engl J Med. 2008;359(15):1543–1554.
    1. van Noord JA, Cornelissen PJ, Aumann JL, Platz J, Mueller A, Fogarty C. The efficacy of tiotropium administered via Respimat soft mist inhaler or HandiHaler in COPD patients. Respir Med. 2009;103(1):22–29.
    1. Vincken W, van Noord JA, Greefhorst AP, et al. Improved health outcomes in patients with COPD during 1 yr's treatment with tiotropium. Eur Respir J. 2002;19(2):209–216.
    1. Voshaar T, Lapidus R, Maleki-Yazdi R, et al. A randomized study of tiotropium Respimat soft mist inhaler vs. ipratropium pMDI in COPD. Respir Med. 2008;102(1):32–41.
    1. Hodder R, Price D. Patient preferences for inhaler devices in chronic obstructive pulmonary disease: experience with Respimat Soft Mist inhaler. Int J Chron Obstruct Pulmon Dis. 2009;4:381–390.
    1. Durham MC. Tiotropium (Spiriva): a once-daily inhaled anticholinergic medication for chronic obstructive pulmonary disease. Proc (Bayl Univ Med Cent) 2004;17(3):366–373.
    1. van Noord JA, Smeets JJ, Custers FL, Korducki L, Cornelissen PJ. Pharmacodynamic steady state of tiotropium in patients with chronic obstructive pulmonary disease. Eur Respir J. 2002;19(4):639–644.
    1. Quanjer PH, Tammeling GJ, Cotes JE, Pedersen OF, Peslin R, Yernault JC. Lung volumes and forced ventilatory flows. Report working party standardization of lung function tests, European Community for Steel and Coal. Official Statement of the European Respiratory Society. Eur Respir J Suppl. 1993;16:5–40.
    1. American Thoracic Society. Standardization of Spirometry, 1994 Update. American Thoracic Society. Am J Respir Crit Care Med. 1995;152(3):1107–1136.
    1. Morais JA, Lobato MR. The new European Medicines Agency guideline on the investigation of bioequivalence. Basic Clin Pharmacol Toxicol. 2010;106(3):221–225.
    1. Price D, Sharma A, Cerasoli F. Biochemical properties, pharmacokinetics and pharmacological response of tiotropium in chronic obstructive pulmonary disease patients. Expert Opin Drug Metab Toxicol. 2009;5(4):417–424.
    1. Ichinose M, Fujimoto T, Fukuchi Y. Tiotropium 5 microg via Respimat and 18 microg via HandiHaler; efficacy and safety in Japanese COPD patients. Respir Med. 2010;104(2):228–236.
    1. SPIRIVA® Respimat®, summary of product characteristics 2012. July 4, 2012.
    1. Dong YH, Lin HH, Shau WY, Wu YC, Chang CH, Lai MS. Comparative safety of inhaled medications in patients with chronic obstructive pulmonary disease: systematic review and mixed treatment comparison meta-analysis of randomised controlled trials. Thorax. 2013;68(1):48–56.
    1. Karner C, Chong J, Poole P. Tiotropium versus placebo for chronic obstructive pulmonary disease. Cochrane Database Syst Rev. 2012;7:CD009285.
    1. Singh S, Loke YK, Enright PL, Furberg CD. Mortality associated with tiotropium mist inhaler in patients with chronic obstructive pulmonary disease: systematic review and meta-analysis of randomised controlled trials. BMJ. 2011;342:d3215.

Source: PubMed

Sponsorer og samarbejdspartnere

Medicinske tilstande

Narkotikainterventioner

3
Abonner